1,2,5-Thiadiazole analogues of aceclidine as potent m1 muscarinic agonists.
The acetyl group of the muscarinic agonist aceclidine 4 was replaced by various 1,2,5-thiadiazoles to provide a new series of potent m1 muscarinic agonists 17 and 18. Optimal m1 muscarinic agonist potency was achieved when the 1,2,5-thiadiazole substituent was either a butyloxy, 17d, or butylthio, 18d, group. Although 1,2,5-oxadiazole 37 and pyrazine 39 are iso-pi-electronic with 1,2,5-thiadiazole 17d, both analogues were substantially less active than 17d. Compounds with high muscarinic affinity and/or m1 muscarinic agonist efficacy were also obtained when the 3-oxyquinuclidine moiety of 17d or 18c was replaced by ethanolamines, hydroxypyrrolidines, hydroxyazetidine, hydroxyisotropanes, or hydroxyazanorbornanes. The structure-activity data support the participation of the oxygen or sulfur atom in the substituent on the 1,2,5-thiadiazole in the activation of the m1 receptor. Several of these new 1,2,5-thiadiazoles have m1 agonist efficacy, potency, and selectivity comparable to those of xanomeline 2 in the muscarinic tests investigated.
Ward
J S
JS
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
Merritt
L
L
Calligaro
D O
DO
Bymaster
F P
FP
Shannon
H E
HE
Mitch
C H
CH
Whitesitt
C
C
Brunsting
D
D
Sheardown
M J
MJ
Olesen
P H
PH
Swedberg
M D
MD
Jeppesen
L
L
Sauerberg
P
P
D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D006868:Hydrolysis; D008297:Male; D051379:Mice; D008958:Models, Molecular; D018721:Muscarinic Agonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism; D011812:Quinuclidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D055672:Static Electricity; D013830:Thiadiazoles / Q000737:chemistry*
D018721:Muscarinic Agonists; D010716:Phosphatidylinositols; D011812:Quinuclidines; D013830:Thiadiazoles; C084650:aceclidine